WO2011141004A1 - Céfodizime hydroxyde de sodium, procédé de préparation de ce composé et utilisations de celui-ci - Google Patents

Céfodizime hydroxyde de sodium, procédé de préparation de ce composé et utilisations de celui-ci Download PDF

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WO2011141004A1
WO2011141004A1 PCT/CN2011/074067 CN2011074067W WO2011141004A1 WO 2011141004 A1 WO2011141004 A1 WO 2011141004A1 CN 2011074067 W CN2011074067 W CN 2011074067W WO 2011141004 A1 WO2011141004 A1 WO 2011141004A1
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low molecular
sodium
hydrate
cefodizime
molecular weight
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PCT/CN2011/074067
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Chinese (zh)
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刘力
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胡梨芳
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms

Definitions

  • the invention relates to the technical field of medicine, in particular to providing an antibacterial drug, cefodizime sodium hydrate, a preparation method and use thereof.
  • Cefodizime sodium is a third-generation cephalosporin for intravenous or intramuscular injection.
  • Cefodizime sodium has broad-spectrum antibacterial activity and has strong antibacterial activity against Gram-negative bacteria such as Klebsiella pneumoniae, Proteus, Shigella, Shigella, Salmonella, Salmonella typhi, Haemophilus influenzae , Gram-positive bacteria such as Staphylococcus, Streptococcus pneumoniae, Streptococcus, Neisseria gonorrhoeae (including penicillin-producing strains), Neisseria meningitidis also has good antibacterial activity.
  • MSSA methicillin-resistant Staphylococcus aureus
  • the thiazole side chain at the 3 position of ceftibizine in cefodizime has good pharmacokinetic properties, and has a long half-life in the human body. It can maintain an effective concentration only once per day for the administration of ⁇ -lactam.
  • the enzyme is more stable and has a unique immunomodulatory effect. In vitro tests have shown that it can enhance the activity of neutrophils, phagocytic cells and lymphocytes, and patients with normal and phagocytic functions (such as elderly patients, multiple myeloma, kidney) In patients with dysfunction, they can enhance their phagocytic function and increase the number of CD 4 lymphocytes, so that the CD 4 /CD ⁇ lymphocyte ratio can return to normal.
  • Cefodizime sodium has a broad-spectrum antibacterial and immunopotentiating effect, and is particularly suitable for infections with low immune function.
  • Cefodizime sodium crystal hydrate and preparation method and use thereof.
  • the cefodizime sodium crystalline hydrate obtained by the present invention surprisingly, The hygroscopicity is much lower than that of cefodizime sodium containing non-crystalline water.
  • the cefodizime sodium containing crystal water is more stable than the crystal water-free, easy to store and transport, and easy to prepare. Further, the deliquescent of the anhydrate causes the air to be prevented from blocking or the like during the treatment, and the hydrate has a good slidability, thereby improving the operability of the preparation.
  • characteristic, thermal analysis of hydrates of the invention (TG-DSC or TG-DTA)
  • the map has a corresponding endothermic peak under the weightless platform, and the thermal analysis map shows cefodizime sodium hydrate, such as cefodizime sodium 0.5 hydrate, 0.6 hydrate, 0.75 hydrate, cefodizime sodium 1 Hydrate, cefodizime sodium 1.5 hydrate, cefodizime sodium 2 hydrate ⁇ cefodizime sodium 2.5 hydrate, and the like.
  • the cefodizime sodium crystal hydrate of the present invention can be stably stored.
  • a sample of cefodizime sodium hydrate and anhydrate was subjected to a wettability test: about 15 g of the cefodizime sodium anhydrate and the hydrate of the present invention were taken. Placed in a dry, constant weight watch glass, precision weighed, 25 °C, relative humidity 70%, respectively, at 0h and 10h Sampling and calculation of the percentage of wet weight gain showed that the anhydrate-free wettability was much higher than that of the hydrate of the present invention, and the cefodizime sodium crystal hydrate of the present invention was more stable and stable. The results are shown in Table 1.
  • Crystalline solids have higher chemical stability and physical stability than amorphous forms and low crystallinity forms, and they may also exhibit improved hygroscopicity, bulk properties, and or flow properties.
  • cefodizime sodium derivative - cefodizime sodium hydrate The preparation of cefodizime sodium derivative - cefodizime sodium hydrate includes the following methods:
  • Method A Adding cefodizin acid to a reaction vessel, adding one of water, a C 1 -C 6 low molecular alcohol, a C 2 -C 8 low molecular ether, a C 2 -C 6 low molecular nitrile or Several kinds, stir, add C 1 -C 12 low molecular amine dropwise at 10 °C, stir and dissolve, add sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium acetate, sodium thiocyanate, sodium octoate, different at 10 °C one or more water-sodium caprylate, C 1 -C 6 lower alcohol is, C 2 -C 8 ether of a low molecular weight, C 3 -C 8 low molecular weight ketones, C 2 -C 8 esters of low molecular weight One or more of the solutions, stirred for 0.2-3 hours, adjusted to a pH of 6.0 to 7.5 with a mineral acid or an organic acid or a solution thereof, and added to the C 1
  • the cefodizin acid used in the reaction C 1 -C 12 low molecular amine: base (sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium acetate, sodium thiocyanate, sodium octoate, sodium isooctanoate)
  • a) molar ratio is generally 1: 0.5 to 1.1: 1 to 1.1
  • cefodizime acid by weight g) water, C 1 -C 6 lower alcohol is, C 2 -C 8 ether of a low molecular weight
  • the ratio of one or several (volume ml) of the C 2 -C 6 low molecular weight nitrile is generally: 1 (g): 1.5 to 50 (ml); water and organic solvent used in crystallization or recrystallization
  • the volume ratio is generally 1: 5 to 300.
  • the amount of activated carbon used is 0.01-1% by weight of the decolorized solution.
  • the molar ratio of cefodizime acid: base (one of sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium acetate, sodium thiocyanate, sodium octanoate, sodium isooctanoate, etc.) used in the reaction is generally 1 : 0.5 ⁇ 1.1 : 1 ⁇ 1.1 ; Cefodizin (weight g) and water, C 1 -C 6 low molecular alcohol, C 2 -C 8 low molecular ether, C 2 -C 6 low molecular nitrile
  • the ratio of one or several (volume ml) is generally: 1 (g): 1.5 to 50 (ml); the volume ratio of water to organic solvent used in crystallization or recrystallization is generally 1:10 to 300 .
  • Adding activated carbon and stirring and decolorizing can be carried out in different processes of preparation.
  • the stirring and decoloring time is generally 10-45 minutes, and the mixture can be decarburized by filtration and washed with water
  • the crystallizing or recrystallization solvent of cefodizime sodium hydrate is selected from the group consisting of water, acetonitrile, tetrahydrofuran, methanol, ethanol, isopropanol, acetone, butyl acetate, ethyl acetate, ethyl formate, diethyl ether, diisopropyl ether, tetrahydrofuran, One or more of dichloromethane, chloroform, etc.; cefodizime sodium crystal crystal or recrystallization solvent, preferably water, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, ethyl acetate, diethyl ether, isopropyl ether, One or several of chloroform.
  • the cefodizime sodium crystal hydrate can be dissolved in water during the recrystallization process, and the activated carbon can be decolorized after dissolution (if the activated carbon is decolored, the amount is 0.01-1% by weight of the decolorized solution) It is further crystallized by the solvent in the present invention.
  • the aqueous solution of cefodizime sodium can be added to the C 1 -C 6 low molecular alcohol, C 2 -C 8 low molecular ether, C 3 -C 8 low molecular ketone, C 2 -C 8 during recrystallization.
  • One or more of the low molecular esters, or a C 1 -C 6 low molecular alcohol, a C 2 -C 8 low molecular ether, a C 3 -C 8 low molecular ketone, C 2 - One or more of a low molecular ester of C 8 and a low molecular halogenated hydrocarbon of C 1 -C 6 are left to cool and crystallize.
  • the preparation of sterile cefodizime sodium hydrate is carried out according to a conventional procedure for aseptic processing.
  • the cefodizime sodium hydrate of the present invention may have different crystal forms.
  • the number of carbon atoms of the low molecular alcohol in the present invention is defined as C 1 -C 6 (ie, an alcohol having 1 to 6 carbon atoms) such as methanol, ethanol, isopropanol, etc.; the number of carbon atoms of the low molecular ether is defined as C 2 -C 8 (ie: an ether of 2-8 carbon atoms) such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, etc.; the number of carbon atoms of the low molecular halogenated hydrocarbon is defined as C 1 -C 6 (ie: a halogenated hydrocarbon of 1 to 6 carbon atoms, including dichloromethane, dichloroethane, chloroform, etc.; the number of carbon atoms of the low molecular ester is defined as C 2 - C 8 (ie: an ester of 2-8 carbon atoms) ), including butyl a
  • the product of the present invention can be dried at different temperatures (e.g., 20-80 ° C), drying time (0.5 Hours to several days), or with other desiccants (including silica gel, phosphorus pentoxide, anhydrous calcium chloride, anhydrous sodium sulfate, etc.) under ambient conditions, or using atmospheric or decompression methods for the final
  • the product is dried. Its drying temperature is preferably 30-50 °C.
  • Powder X-ray diffraction is commonly used to characterize and/or identify polymorphs, for powder X-ray diffraction in characterization and / Or when identifying, use the modifier 'about' before reporting the peak. This is a common practice in the field of solid state chemistry due to the inherent variations in peaks.
  • the typical accuracy of the 2 ⁇ x-axis value of the powder peak is ⁇ 0.2° 2 ⁇ Level, therefore, the powder X diffraction peak appearing at 'about 8.0 ° 2 ⁇ means that when measured on most X-ray diffractometers, the peaks may be at 7.8 ° 2 ⁇ and 8.2 ° 2 ⁇ .
  • the change in peak intensity is the result of how each crystal is oriented in the sample container relative to the external X-ray source, and the orientation does not provide structural information about the crystal.
  • the invention provides a different crystalline hydrate of cefodizime sodium.
  • the invention provides crystalline hydrates of different crystalline forms and methods for their preparation.
  • the invention provides a pharmaceutical composition comprising any one or more of cefodizime sodium prepared by the method of the invention A crystalline hydrate, and one or more pharmaceutically acceptable excipients.
  • the invention further provides a process for the preparation of a pharmaceutical formulation comprising any one or more of cefodizime sodium prepared by the process of the invention Crystalline hydrate.
  • the present invention further provides cefodizime sodium crystal hydrate and crystalline hydrates of different crystal forms, such as cefodizime sodium 1 hydrate, 1.5 Use of hydrates, hydrates, 2.5 hydrates, and the like, in the preparation of a pharmaceutical composition for the treatment of infections, including bacterial infections, Gram-positive and or Gram-negative infections.
  • cefodizime sodium hydrate of the present invention is used for preparing a solid preparation, an injection, wherein the injection includes Injectable lyophilized powder preparation, aseptic dispensing powder preparation, infusion preparation (including double chamber, large infusion, non-PVC solid-liquid double chamber, large infusion, non-PVC multi-layer co-extruded film) That is, matching large infusion), Tablets, capsules, granules, etc.; and can be used to prepare cefodizime sodium anhydrate.
  • the injection includes Injectable lyophilized powder preparation, aseptic dispensing powder preparation, infusion preparation (including double chamber, large infusion, non-PVC solid-liquid double chamber, large infusion, non-PVC multi-layer co-extruded film) That is, matching large infusion), Tablets, capsules, granules, etc.; and can be used to prepare cefodizime sodium anhydrate.
  • the preparation of the anhydrate can be obtained by the cefodizime sodium hydrate of the present invention by different drying methods, and the preparation can be carried out at different temperatures (such as 50-100 °C), drying time (hours to days), or with other desiccants (including silica gel, molecular sieves, phosphorus pentoxide, sodium hydroxide, anhydrous sodium carbonate, anhydrous calcium chloride, anhydrous sodium sulfate,
  • the final product may be dried under ambient conditions or under normal pressure or reduced pressure, or may be first distilled from benzene with water and dried in combination with other drying methods described herein. obtain.
  • tablets including buccal tablets, sublingual tablets, oral patches, orally disintegrating tablets, vaginal tablets, etc.
  • capsules including rectal, vaginal capsules, etc.
  • granules which may contain pharmaceutically acceptable Fillers such as starch, modified starch, lactose, microcrystalline cellulose, cyclodextrin, sorbitol, mannitol, calcium phosphate, amino acids, etc.; pharmaceutically acceptable disintegrating agents such as starch, modified starch, microcrystalline fiber , sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, surfactant (sodium lauryl sulfate, etc.); pharmaceutically acceptable wetting agents and binders, such as gums Starch, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyvinylpyrrolidone, alginic acid and its salts; pharmaceutically acceptable lubricants and glidants such as
  • Preparation method mixing main drug with matrix The water bath is heated, stirred, and to be melted, stirred until evenly, and poured into the mold of the suppository coated with the lubricant to slightly overflow the plug mold, and then flattened after cooling, and the mold is obtained.
  • cefodizime sodium hydrate which is prepared by:
  • Infusion preparations including double chamber, large infusion, non-PVC solid-liquid dual-chamber, large infusion, non-PVC
  • a large infusion solution made of a multi-layer co-extruded film is prepared in a conventional manner.
  • the preparation method of the lyophilized powder preparation is as follows: taking cefodizime sodium hydrate, adding pharmaceutically acceptable lyophilized support agent or auxiliary agent, stabilizer, water for injection, stirring to dissolve, if necessary, pharmaceutically acceptable Accepted acid and base to adjust the pH to 6.0 ⁇ 7.5, add activated carbon 0.005 ⁇ 0.5% (W / V) stirring 15 ⁇ 45min, filtration, hydration, sterile filtration, press 0.5 ⁇ 2g / Bottles are packed, freeze-dried, and tamponed to obtain finished products.
  • the regulator may be a pharmaceutically acceptable inorganic or organic acid, an inorganic base or an organic base, or a Lewis acid or a base in a broad sense, and may contain one or more of them, and may be hydrochloric acid, phosphoric acid, propionic acid, acetic acid or the like.
  • Acetate such as sodium acetate, lactic acid and lactic acid pharmaceutically acceptable salt, citric acid pharmaceutically acceptable salt, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, phosphate, tartaric acid and medicinal use thereof Salt, borax, boric acid, succinic acid, caproic acid, adipic acid, fumaric acid, maleic acid, polyhydroxycarboxylic acid and pharmaceutically acceptable salts such as glucuronic acid, gluconic acid, lactobionic acid, apple One or more of acid, threonic acid, glucoheptonic acid and the like.
  • the pharmaceutically acceptable antioxidants and stabilizers thereof may be sulfurous acid, sulfite, bisulfite, pyrosulfite, dithionite, thiosulfate, organic sulfur compound thiourea, glutathione Glycopeptide, dimercaptopropanol, thioglycolic acid and salt, thiolactic acid and salt, thiodipropionic acid and salt, phenolic compounds such as gallic acid and salt, caffeic acid, caffeate, ferulic acid, awei Acid salt, di-tert-butyl-p-phenol, 2 , 5-dihydroxybenzoic acid, 2 , 5- Dihydroxybenzoate, phenol or its derivative, salicylic acid or its salt; ascorbic acid and ascorbate, isoascorbic acid and isoascorbate, nicotinamide, tartaric acid, nitrate, phosphate, pharmaceutically acceptable salt, citric acid Salt, EDTA And one or
  • the ultrafilter may be a flat plate type, a coil type, a tube type, a hollow fiber type or a round box type, etc., preferably a roll type and a hollow fiber type ultrafilter, and the molecular weight of the interception is 50,000 to 300,000.
  • the filter removes the remaining heat source by using an ultrafiltration membrane with a molecular weight of 4,000 to 30,000, preferably an ultrafiltration membrane having a molecular weight of 6000 to 30,000.
  • the cefodizime sodium hydrate of the invention is suitable for: preparing a respiratory system, hepatobiliary system, facial features, of human or animal caused by Gram-positive or negative bacteria-sensitive bacteria Urinary tract infection, abdominal infection, pelvic infection, sepsis, skin and soft tissue infection, bone and joint infection, uterine annexitis, intrauterine infection, paragangal connective tissue inflammation, meningitis, gonorrhea The use of drugs for the treatment or prevention of diseases.
  • the present invention further provides a composition of cefodizime sodium hydrate and a ⁇ -lactamase inhibitor, cefodizime sodium hydrate
  • the beta-lactamase inhibitor comprises a pharmaceutically acceptable salt of tazobactam or a pharmaceutically acceptable salt of sulbactam or clavulanic acid.
  • Medicinal salts such as tazobactam sodium, tazobactam sodium hydrate, sulbactam sodium, clavulanate potassium, and the like.
  • Cefodizime sodium crystalline hydrate and enzyme inhibitors include pharmaceutically acceptable salts of tazobactam or pharmaceutically acceptable salts of sulbactam Or the pharmaceutically acceptable salt composition of clavulanic acid has a weight ratio of 30:1 to 1:2.
  • the weight ratio of the composition of cefodizime sodium hydrate to the ⁇ -lactamase inhibitor may vary depending on the ⁇ - The ratio of the lactamase inhibitor varies, and the weight ratio of the combination of cefodizime sodium hydrate and the ⁇ -lactamase inhibitor tazobactam or a pharmaceutically acceptable salt thereof is preferably 4:1 to 8:1.
  • the weight ratio of the general cefodizime sodium hydrate to the ⁇ -lactamase inhibitor sulbactam or a pharmaceutically acceptable salt thereof is preferably 2:1 to 1 :1
  • the composition has a stronger antibacterial action and is used in a medicament for treating or preventing a human or animal disease caused by a Gram-positive or a negative bacterial-sensitive bacterium.
  • Dosage usage Under normal circumstances, for cefodizime sodium hydrate (based on anhydrous matter), the adult dosage is generally 1.0 ⁇ 2.0g per day. It is administered in 1-2 times; the dosage of children is generally 60 ⁇ 80mg/kg per day, which can be increased or decreased according to the symptoms.
  • Intravenous 0.5g or 1.0g solution in 4ml water for injection, or 2.0g Dissolve in 10ml water for injection and inject within 3 to 5 minutes.
  • Intravenous infusion 0.5g, 1.0g or 2.0g dissolved in 40ml water for injection, normal saline or Ringer's solution, Infusion within 20 to 30 minutes.
  • Intramuscular injection 0.5g or 1.0g dissolved in 4ml water for injection, or 2.0g dissolved in 10ml Injecting water
  • deep gluteal muscle injection To prevent pain, cefodizime sodium hydrate can be dissolved in 1% lidocaine solution.
  • oral administration change the route of injection for absorption through the oral mucosa
  • adult daily 0.5 g to 2 g or vaginal administration (absorbed through the vaginal mucosa), or rectal administration, 0.5 g to 2 g per day for adults.
  • the cefodizime sodium hydrate of the present invention comprises a crystalline hydrate and a non-crystalline hydrate, and is suitable for: preparing an antibacterial combination drug, which comprises cefodizime sodium hydrate and clavulanic acid or a pharmaceutically acceptable salt thereof, sulba Or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, wherein cefodizime sodium hydrate and The weight ratio of the ⁇ -lactamase inhibitor is 1:0.0 5 to 2, and the pharmaceutically acceptable salt of clavulanic acid is preferably potassium clavulanate or pharmaceutically acceptable salt of sulbactam, preferably sulbactam sodium, tazobactam medicinal salt Tazobactam sodium.
  • the crystalline hydrate of the present invention is different from The deliquescent of the anhydrate prevents the air from being blocked during the treatment, and the crystallization hydrate has good slidability, thereby improving the operability of the preparation; and preparing the solid preparation It has good dissolution properties, making it easy to be absorbed into the blood circulation, improving bioavailability, and facilitating its rapid function. On the other hand, it is prevented from appearing in the case of aseptic dispensing, which is not easy to cause clogging due to moisture absorption, resulting in a difference in the amount of the load, resulting in insufficient dosage, resulting in product failure, or because of unqualified products.
  • the antibacterial combination drug can be used for an infectious disease caused by Gram-positive or negative bacteria which is less sensitive to cefodizime sodium hydrate but has enhanced sensitivity after using the above enzyme inhibitor, and the above composition is suitable for preparation Human or animal respiratory system, hepatobiliary system, facial features, urinary tract infection, abdominal infection, pelvic infection, sepsis, skin and soft tissue infection, bone and joint infection, uterine annexitis, intrauterine infection, paragangal connective tissue inflammation , meningitis, gonorrhea The use of drugs for the treatment or prevention of diseases.
  • Figure 1 is a thermogram of cefodizime sodium 1 hydrate.
  • Figure 2 is a thermogram of cefodizime sodium 1.5 hydrate.
  • Figure 3 is a thermogram of cefodizime sodium 2 hydrate.
  • Figure 4 is a thermogram of cefodizime sodium 2.5 hydrate.
  • Figure 5 is a powder X-ray diffraction pattern of cefodizime sodium 1.5 hydrate hydrate (Example 3).
  • Figure 6 is a powder X-ray diffraction pattern of cefodizime sodium 2.5 hydrate (Example 7).
  • the term 'obtained' refers to a compound isolated at a valuable level of purity, including but not limited to greater than 90%. , 95%, 96%, 97%, 98%, and 99% purity levels.
  • the purity level can be determined by high performance liquid chromatography.
  • Thermal analysis test conditions Setaram Setsys 16 , sample volume of about 5mg, heating rate: 10K / min, N 2 flow rate: 50ml / min, temperature: room temperature ⁇ 400 ° C or so.
  • characteristic, thermal analysis of hydrates of the invention (TG-DTA) Or the TG-DSC) map has a corresponding endothermic peak under the weightless platform.
  • the cefodizime sodium 1.5 hydrate of the present invention may have a corresponding characteristic value at a position including the following 2 ⁇ values (Fig. 5): about 3.77, 10.19, 16.91, 21.7.
  • the cefodizime sodium 2.5 hydrate of the present invention may have a corresponding characteristic value at a position including the following 2 ⁇ values (Fig. 6) about 4.47, 6.16, 9.97 , 11.95, 16.26, 19.88, 21.91.
  • composition refers to a composition of a drug, which may contain at least one pharmaceutically acceptable carrier.
  • Example 1 Preparation of Cefodizime Sodium 1 Hydrate 10 g of cefodizime acid and 30 ml of water were added to a reaction flask, and the mixture was stirred to form a suspension. 5 ml of triethylamine was added dropwise at 5 ° C, stirred for 30 min, and dropped at 5 ° C. Add 28% sodium isooctanoate in ethanol to adjust the pH to 6.9 (after adding more, adjust the pH to 6.9 with glacial acetic acid), stir, slowly add 50 ml of acetone and 150 ml of acetonitrile, and place at -5 ° C to make the solids be analyzed.
  • Example 2 Preparation of Cefodizime Sodium 1 Hydrate 10 g of cefodizin acid and 30 ml of water were added to a reaction flask, and the mixture was stirred to form a suspension. 3.8 ml of diethylamine was added dropwise at 5 ° C, stirred to dissolve, and activated carbon was added.
  • Example 3 Preparation of Cefodizime Sodium 1.5 Hydrate 20 g of cefodizin acid and 50 ml of water were added to a reaction flask, and the mixture was stirred to form a suspension, and a saturated aqueous solution of 3.8 g of anhydrous sodium carbonate was added dropwise at 5 ° C to adjust the pH to 7.0 (after adding more, adjust the pH to 7.0 with glacial acetic acid), stir, add 0.3g of activated carbon, stir for 30 minutes, suction filtration, wash with water, suction filtration, slowly add 50ml of acetone and 250ml of isopropyl ether in the filtrate, 4°C Placed below, the solid is charged and analyzed, suction filtered, acetone washed 3 times, suction filtration, the solid obtained is dissolved with a small amount of water, 0.3 g of activated carbon is added, stirred for 30 minutes, suction filtered, washed with water, suction filtered, with isoprop
  • the retention time of HPLC is consistent with the HPLC retention time of the cefodizin acid reference substance; melting point: 192 ° C discoloration (ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected), X powder diffraction: multiple measurements in the range of 3-60 ° Obvious characteristic peak, Karl Fischer method Divided into 4.15%, thermal analysis: platform weight loss is about 3.93% ( Figure 2), which is within the error range of the sample containing 1.5 crystal water (theoretical value 4.12%); X powder diffraction: in the range of 3-60 ° The determination has a number of distinct characteristic peaks (Fig.
  • Example 4 Preparation of Cefodizime Sodium 1.5 Hydrate 20 g of cefodizin acid, 5 ml of water and 200 ml of methanol were added to the reaction flask, and the mixture was stirred, and a solution of 28% sodium isooctanoate in ethyl acetate was added dropwise at 5 ° C to adjust the pH to 7.0. Stir, slowly add 280 ml of acetone, 150 ml of isopropyl ether, and place at -5 ° C or lower.
  • the solid is charged and analyzed, suction filtered, acetone washed 3 times, suction filtered, and the obtained solid is dissolved with a small amount of water, 0.3 g of activated carbon is added. After stirring for 30 minutes, suction filtration, the filtrate was added with acetone 300 ml, acetonitrile 420 ml, and isopropyl ether 80 ml as a crystallization solvent for recrystallization. The mixture was allowed to stand at 5 ° C or less overnight, and the crystals were analyzed by suction, suction filtration, 40 ml of chloroform, suction filtration, vacuum at 40 ° C.
  • Example 5 Preparation of Cefodizime Sodium 2 Hydrate 20 g of cefodizin acid, 5 ml of water and 100 ml of methanol were added to a reaction flask, stirred, and a solution of 28% sodium isooctanoate in isopropanol was added dropwise at 5 ° C to adjust the pH to 6.8.
  • HPLC purity: 99.4 %, the retention time of HPLC is consistent with the HPLC retention time of cefodizin acid reference substance; melting point: 168 ° C discoloration (ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected), specific rotation: -58.8 ° (take this product, accurately weighed Dissolve in water and quantitatively dilute to make a solution containing about 10 mg per 1 ml); the moisture content is 5.66% by Karl Fischer method, thermal analysis: platform weight loss is about 5.80% (Fig. 3), which is the result of the sample containing 2 crystal water.
  • Example 6 Preparation of Cefodizime Sodium 0.5 Hydrate 20 g of cefodizime acid and 50 ml of water were added to a reaction flask, and the mixture was stirred to form a suspension, and a saturated aqueous solution of 5.8 g of sodium hydrogencarbonate was added dropwise thereto at 5 ° C to dissolve.
  • Example 7 Preparation of Cefodizime Sodium 2.5 Hydrate 10 g of cefodizin acid and 30 ml of water were added to a reaction flask, and the mixture was stirred to form a suspension. A saturated aqueous solution of sodium carbonate was added dropwise at 5 ° C to adjust the pH to about 7.2, and stirred. Add 0.3g of activated carbon, stir for 30 minutes, suction filtration, wash with water, suction filtration, slowly add 200 ml of acetone and 200 ml of isopropanol in the filtrate, and place it at 15 ° C or lower to make the solids be analyzed, suction, and wash with isopropyl alcohol 3 times.
  • the obtained solid was dissolved in a small amount of water, 0.3 g of activated carbon was added, stirred for 30 minutes, suction filtered, washed with water, suction filtered, and recrystallized with 200 ml of isopropyl alcohol and 200 ml of acetone, and left at 10 ° C overnight.
  • Example 8 Take cefodizime sodium hydrate 100g, stir to dissolve, add mannitol 20g, EDTA disodium 0.05g, add 40 ⁇ 500 ml of water for injection, stir to dissolve, adjust the pH to 6.0 ⁇ 7.5 with 1-5M citric acid and disodium hydrogen phosphate solution, add activated carbon 0.01 to 0.5% (W/V), stir for 15-30min, filter, filter with 0.22 micron microporous membrane, press 0.5g / bottle or 1g / Bottles are packed, vacuum freeze-dried, and tamponed to obtain finished products.
  • Example 9 Take sterile cefodizime sodium hydrate 10Kg in an aseptic packaging process at 0.5g / bottle or 0.75g / Bottle or 1g / bottle or 2g / bottle is divided, stoppered, plugged, rolled aluminum cover finished product.
  • Example 10 Take sterile cefodizime sodium 1 hydrate 2Kg in the aseptic packaging process according to the main drug 0.5g / bottle or 1g / bottle or 1.5g / bottle is divided, stoppered, plugged, rolled aluminum cover finished product.
  • cefodizime sodium 1 hydrate, lactose, sodium carboxymethyl starch was passed through a 100 mesh sieve and mixed, using 5 % PVP 30
  • a suitable amount of 50% ethanol aqueous solution is a soft material made of a binder.
  • the granules are sieved through 18 - 24 mesh, dried, and sieved through a 14 - 20 mesh sieve, and then mixed with magnesium stearate, tableted or filled.
  • Cefodizime sodium hydrate prepared according to the method of Example 1 or Example 2 or Example 3 or Example 4 Or the method of Example 5 or the method of Example 6 or the method of Example 7), instant sorbitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate over 100 mesh sieve, mixed, pressed into Large piece, then press the piece The pellets were sieved into 18 - 24 mesh screens.
  • Example 15 Preparation of cefodizime sodium hydrate vaginal capsule of the present invention (main drug 125 mg/granule)
  • Cefodizime sodium hydrate prepared according to Example 1 or Example 2 or Example 3 or Example 4 or Example 5
  • the method or the preparation method 6 is prepared by passing through a 100 mesh sieve, mixing, and filling the capsule.
  • Cefodizime sodium crystal hydrate prepared by the method of Example 1, glycerin, stearic acid polyoxyl (40 ), fat, poloxamer mixture, heated in a water bath, stirred, to be melted, stirred until evenly, quickly poured into the mold of the lubricant-coated suppository, to slightly overflow the plug mold, to be flat after cooling, the mold is obtained .
  • Cefodizime sodium crystal hydrate prepared according to Example 1 or Example 2 or Example 3 or Example 4 Method or Example 5 Method or Example 6 Preparation Preparation
  • Glycerin Polyethylene Glycol 1500, Polyethylene Glycol 4000, Poloxamer, EDTA Mix the disodium, heat in a water bath, stir, melt, stir until it is evenly poured into the mold of the suppository that has been coated with the lubricant, until it is slightly spilled, and then flattened after cooling.
  • Example 18 Sterile cefodizime sodium 1 hydrate and tazobactam sodium (8:1) 100 under GMP conditions ⁇ According to the preparation procedure of powder injection, it is divided into 50-200 bottles, stoppered, plugged, and rolled to obtain the finished product.
  • Example 19 Sterile cefodizime sodium 2.5 hydrate and tazobactam sodium (4:1) under GMP conditions 100 g According to the preparation procedure of powder injection, it is divided into 50-200 bottles, stoppered, pressed, and rolled to obtain the finished product.
  • Example 20 100 g of sterile cefodizime sodium 1 hydrate and sterile sulbactam sodium under GMP conditions 25g is fully mixed and processed according to the powder injection preparation process. It is divided into 50-200 bottles, stoppered, plugged, and rolled to obtain the finished product.
  • Example 21 100 g of sterile cefodizime sodium 1.5 hydrate with sterile sulbactam sodium under GMP conditions 50g is fully mixed and processed according to the powder injection preparation process. It will be packed into 50-200 bottles, stoppered, plugged, and rolled to obtain the finished product.
  • Example 22 sterilized cefodizime sodium 2 hydrate 100 g under sterile GMP conditions with sterile sulbactam sodium 100g is fully mixed and processed according to the powder injection preparation process. It will be packed into 50-200 bottles, stoppered, plugged, and rolled to obtain the finished product.
  • Example 23 100 g of sterile cefodizime sodium 1 hydrate and sterile potassium clavulanate under GMP conditions 5g is fully mixed and fully mixed. According to the powder injection preparation process, it is divided into 50-200 bottles, stoppered, plugged, rolled aluminum cover to obtain the finished product.
  • Example 24 100 g of sterile cefodizime sodium 2 hydrate and sterile sulbactam sodium under GMP conditions 50g is fully mixed and processed according to the preparation procedure of lyophilized powder injection. It will be packed into 50-200 bottles, stoppered, freeze-dried, tamped, and rolled to obtain the finished product.
  • Example 25 Determination of the minimum inhibitory concentration of cefodizime sodium 1 hydrate by double dilution method MIC, MIC 50 and MIC 90 are as follows:
  • Example 26 Determination of cefodizime sodium by double dilution method 1.5 Minimum inhibitory concentration of hydrate MIC, MIC50 And the MIC90 is as follows
  • Example 26 Determination of cefodizime sodium 2 hydrate by double dilution method The minimum inhibitory concentration of MIC, MIC 50 and MIC 90 is as follows
  • E. coli (6) Pneumococcal (6) Cefodizime sodium 1 hydrate (Example 1 method): sulbactam sodium (2: 1) 0.003 ⁇ 0.06 0.006 ⁇ 0.012 Cefodizime sodium 1.
  • 5 hydrate (Example 3 method): potassium clavulanate (2: 1) 0.003 ⁇ 0.06 0.006 ⁇ 0.012 Cefodizime sodium 2 hydrate
  • Example 5 method sulbactam sodium (2: 1) 0.003 ⁇ 0.06 0.006 ⁇ 0.012 Cefodizime sodium 1.
  • Example 3 method sulbactam sodium (2: 1) 0.006 ⁇ 0.015 0.003 ⁇ 0.06 Cefodizime sodium 2.5 hydrate
  • Example 7 method tazobactam sodium (8: 1) 0.003 to 0.006 0.003 ⁇ 0.06
  • cefodizime sodium hydrate was prepared according to the specific examples.

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Abstract

L'invention concerne le composé céfodizime hydroxyde de sodium, un procédé de préparation de ce composé et des utilisations de celui-ci. Ledit composé présente une meilleure stabilité au stockage et peut être utilisé pour produire des médicaments destinés à prévenir ou à traiter, chez l'être humain ou l'animal, des maladies associées à une infection du système respiratoire, à une infection du système hépatobiliaire, à des infections des cinq organes sensoriels et des voies urinaires, à une infection de la cavité abdominale, à une infection pelvienne, à l'ichorrhémie, à une infection des tissus mous, à une infection osseuse et articulaire, à une infection des annexes de l'utérus, à une infection intra-utérine, à une infection paramétriale, à la méningite et à la gonorrhée et analogue, qui sont dues à des bactéries à Gram-positif ou négatif.
PCT/CN2011/074067 2010-05-13 2011-05-13 Céfodizime hydroxyde de sodium, procédé de préparation de ce composé et utilisations de celui-ci WO2011141004A1 (fr)

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CN101830915A (zh) * 2010-05-13 2010-09-15 胡梨芳 头孢地嗪钠水合物及其制备方法和用途
CN103110641A (zh) * 2013-02-04 2013-05-22 海南中元堂医药科技有限公司 一种注射用头孢地嗪钠和盐酸利多卡因注射液的药物组合物
CN104327099A (zh) * 2014-09-29 2015-02-04 联合康兴（北京）医药科技有限公司 头孢哌酮钠化合物实体及组合物和用途
CN110327284B (zh) * 2019-07-18 2022-11-22 石药集团中诺药业（石家庄）有限公司 一种注射用头孢地嗪钠及其制备方法

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US4590267A (en) * 1981-11-03 1986-05-20 Hoechst Aktiengesellschaft Crystalline disodium salt of cefodizim
CN1565457A (zh) * 2003-06-21 2005-01-19 张哲峰 一种抑制β－内酰胺酶的抗菌组合药物
CN101239985A (zh) * 2008-03-12 2008-08-13 齐鲁安替制药有限公司 头孢地嗪钠的制备方法
CN101723958A (zh) * 2008-10-22 2010-06-09 丽珠医药集团股份有限公司 头孢地嗪钠药物及制备方法
CN101830915A (zh) * 2010-05-13 2010-09-15 胡梨芳 头孢地嗪钠水合物及其制备方法和用途

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DE3911322A1 (de) * 1989-04-07 1990-10-11 Hoechst Ag Verfahren zur herstellung von cefodizim-dinatrium

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US4590267A (en) * 1981-11-03 1986-05-20 Hoechst Aktiengesellschaft Crystalline disodium salt of cefodizim
CN1565457A (zh) * 2003-06-21 2005-01-19 张哲峰 一种抑制β－内酰胺酶的抗菌组合药物
CN101239985A (zh) * 2008-03-12 2008-08-13 齐鲁安替制药有限公司 头孢地嗪钠的制备方法
CN101723958A (zh) * 2008-10-22 2010-06-09 丽珠医药集团股份有限公司 头孢地嗪钠药物及制备方法
CN101830915A (zh) * 2010-05-13 2010-09-15 胡梨芳 头孢地嗪钠水合物及其制备方法和用途

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